TY - JOUR
T1 - Cytoplasmic “ciliary inclusions” in isolation are not sufficient for the diagnosis of primary ciliary dyskinesia
AU - Vece, Timothy J.
AU - Sagel, Scott D.
AU - Zariwala, Maimoona A.
AU - Sullivan, Kelli M.
AU - Burns, Kimberlie A.
AU - Dutcher, Susan K.
AU - Yusupov, Roman
AU - Leigh, Margaret W.
AU - Knowles, Michael R.
N1 - Funding Information:
The authors thank the children and their families that participated in this study. We thank Whitney Wolf for technical assistance and Dr Hong Dang for bioinformatics assistance. We thank Srikanth Mane, Francesc Lopez-Giraldez, and Weilai Dong from Yale Center for Mendelian Genomics (UM1 HG006504) and McDonnell Genome Institute, Washington University, St Louis for providing WES and bioinformatics support. We thank Eric Wartchow for his assistance in connecting us with some patients through their treating clinicians. TJV, SDS, MAZ, KMS, MWL, and MRK were funded by NIH-NHLBI (grant U54HL096458); SDS by NIH-NCATS (grant UL1TR001082); SKD by NIH-NHLBI (grant 5R01HL12837004); MAZ, MWL, and MRK by NIH-NHLBI (grant R01HL071798). The Genetic Disorders of Mucociliary Clearance (U54HL096458) is a part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and NHLBI.
Funding Information:
The authors thank the children and their families that participated in this study. We thank Whitney Wolf for technical assistance and Dr Hong Dang for bioinformatics assistance. We thank Srikanth Mane, Francesc Lopez‐Giraldez, and Weilai Dong from Yale Center for Mendelian Genomics (UM1 HG006504) and McDonnell Genome Institute, Washington University, St Louis for providing WES and bioinformatics support. We thank Eric Wartchow for his assistance in connecting us with some patients through their treating clinicians. TJV, SDS, MAZ, KMS, MWL, and MRK were funded by NIH‐NHLBI (grant U54HL096458); SDS by NIH‐NCATS (grant UL1TR001082); SKD by NIH‐NHLBI (grant 5R01HL12837004); MAZ, MWL, and MRK by NIH‐NHLBI (grant R01HL071798). The Genetic Disorders of Mucociliary Clearance (U54HL096458) is a part of the NCATS Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research (ORDR), NCATS, funded through a collaboration between NCATS and NHLBI.
Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Background: The diagnosis of primary ciliary dyskinesia (PCD) is difficult and requires a combination of clinical features, nasal nitric oxide testing, cilia ultrastructural analysis by electron microscopy (EM), and genetics. A recently described cytoplasmic ultrastructural change termed “ciliary inclusions” was reported to be diagnostic of PCD; however, no supporting evidence of PCD was provided. In this study, we sought to confirm, or refute, the diagnosis of PCD in subjects with “ciliary inclusions” on EM. Methods: Six subjects from five families with previous lab reports of “ciliary inclusions” on EMs of ciliated cells were identified and evaluated at a Genetic Disorders of Mucociliary Clearance Consortium site. We performed a detailed clinical history, nasal nitric oxide measurement, genetic testing including whole-exome sequencing (WES), and when possible, repeat ciliary EM study. Results: Only one of six subjects had multiple and persistent clinical features congruent with PCD. No subject had situs inversus. Only one of six subjects had a very low nasal nitric oxide level. No “ciliary inclusions” were found in three subjects who had a repeat ciliary EM, and ciliary axonemal ultrastructures were normal. Genetic testing, including WES, was negative for PCD-causing genes, and for pathogenic variants in gene pathways that might cause “ciliary inclusions,” such as ciliary biogenesis. Conclusion: “Ciliary Inclusions”, in isolation, are not sufficient to diagnosis PCD. If seen, additional studies should be done to pursue an accurate diagnosis.
AB - Background: The diagnosis of primary ciliary dyskinesia (PCD) is difficult and requires a combination of clinical features, nasal nitric oxide testing, cilia ultrastructural analysis by electron microscopy (EM), and genetics. A recently described cytoplasmic ultrastructural change termed “ciliary inclusions” was reported to be diagnostic of PCD; however, no supporting evidence of PCD was provided. In this study, we sought to confirm, or refute, the diagnosis of PCD in subjects with “ciliary inclusions” on EM. Methods: Six subjects from five families with previous lab reports of “ciliary inclusions” on EMs of ciliated cells were identified and evaluated at a Genetic Disorders of Mucociliary Clearance Consortium site. We performed a detailed clinical history, nasal nitric oxide measurement, genetic testing including whole-exome sequencing (WES), and when possible, repeat ciliary EM study. Results: Only one of six subjects had multiple and persistent clinical features congruent with PCD. No subject had situs inversus. Only one of six subjects had a very low nasal nitric oxide level. No “ciliary inclusions” were found in three subjects who had a repeat ciliary EM, and ciliary axonemal ultrastructures were normal. Genetic testing, including WES, was negative for PCD-causing genes, and for pathogenic variants in gene pathways that might cause “ciliary inclusions,” such as ciliary biogenesis. Conclusion: “Ciliary Inclusions”, in isolation, are not sufficient to diagnosis PCD. If seen, additional studies should be done to pursue an accurate diagnosis.
KW - cilia EM
KW - ciliary inclusions
KW - primary ciliary dyskinesia
UR - http://www.scopus.com/inward/record.url?scp=85074425739&partnerID=8YFLogxK
U2 - 10.1002/ppul.24528
DO - 10.1002/ppul.24528
M3 - Article
C2 - 31549486
AN - SCOPUS:85074425739
SN - 8755-6863
VL - 55
SP - 130
EP - 135
JO - Pediatric Pulmonology
JF - Pediatric Pulmonology
IS - 1
ER -